1. Field of the Invention
The present invention relates to methods and materials for assessing prostate cancer therapies.
2. Description of Related Art
Cancer is the second leading cause of human death next to coronary disease. Worldwide, millions of people die from cancer every year. In the United States alone, as reported by the American Cancer Society, cancer causes the death of well over a half-million people annually, with over 1.2 million new cases diagnosed per year. While deaths from heart disease have been declining significantly, those resulting from cancer generally are on the rise. In this century, cancer is predicted to become the leading cause of death.
Worldwide, several cancers stand out as the leading killers. In particular, carcinomas of the lung, prostate, breast, colon, pancreas, and ovary represent the primary causes of cancer death. These and virtually all other carcinomas share a common lethal feature. With very few exceptions, metastatic disease from a carcinoma is fatal. Moreover, even for those cancer patients who initially survive their primary cancers, common experience has shown that their lives are dramatically altered.
Adenocarcinoma of the prostate is the most frequently diagnosed cancer in men in the United States, and is the second leading cause of male cancer deaths (Karp et al., Cancer Res. 56:5547-5556 (1996)). Therapy for prostate cancer is typically initiated using hormone drugs that lower serum testosterone, often given in combination with competitive androgen receptor (AR) antagonists. Although initially effective at blocking tumor growth, these therapies eventually fail, leading to a drug resistant stage called androgen independent or hormone refractory (HR) disease that is uniformly lethal.
Postulated mechanisms to explain resistance to hormone therapy can be separated into three general categories.1-3 The first includes DNA-based alterations in the AR gene such as amplification or point mutations, which collectively only occur in a minority of patients.4-7 A subset of these AR mutations map to the ligand binding domain (LBD) and are proposed to cause resistance by altering the response of the receptor such that noncanonical ligands like estrogen or hydrocortisone, or even AR antagonists like flutamide, behave as agonists.8,9 Although their clinical association with antiandrogen resistance is strong, the overall frequency of AR amplification or mutation cannot account for most cases of hormone refractory disease.
The second category applies to the majority of patients without AR gene mutation or amplification who retain active AR signaling. Increased mitogen-activated protein kinase signaling mediated by oncogenes such as ErbB2 or Ras can cause ligand-independent activation of AR.10,11 The kinases and substrates responsible for AR activation in this setting are unknown, but this is presumed to occur through downstream phosphorylation of AR-associated proteins or AR itself, analogous to the estrogen receptor (ER).12-14 Similarly, alteration in the balance of coactivators or corepressors can affect AR activation,15,16 based on similar findings for ER.17 The relative frequency of these events and their relationship to clinical drug resistance remain to be defined.
The third category of hormone resistance mechanisms is based on the concept that the pro-growth and survival functions of AR can be “bypassed” by alternative signaling pathways, such that AR is no longer relevant to disease progression. One example is upregulation of the anti-apoptotic gene Bcl-2 in late stage clinical samples,18,19 but functional proof of a role in hormone resistance is lacking. The AR bypass hypothesis is also consistent with observations of AR gene methylation leading to decreased or absent AR expression in some HR cancers,20 as well as reports that androgen induces growth arrest or apoptosis in certain contexts.21,22 
Collectively, these data implicate multiple mechanisms by which prostate cancers acquire resistance to hormone therapy and highlight the continuing debate about the role of AR in late stage disease progression. Consequently, there is a need in the art for models that reproduce clinically significant aspects of this disease progression, particularly the transition from the initial stage in the prostate cancer where the cancer cells are sensitive to hormone antagonists to the subsequent drug resistant stage. In particular, a well-defined and manipulatable cell based model is needed to dissect the molecular events associated with the progression from a drug sensitive to a drug resistant phase. In addition, there is a need in the art for cell based prostate cancer models that reproduce the drug sensitive and/or drug resistant phases of cancers of the prostate that can be used, for example in the evaluation of new therapeutic modalities. The invention disclosed herein satisfies this need.